Diabetes has reached epidemic proportions in much of the western world and is a serious and growing public health concern in many developing economies. Globally, there are approximately 285 million people with diabetes and that number is expected to reach 438 million by 2030 (IDF Diabetes Atlas, 2009.)
Diabetes complications are usually associated with chronically elevated blood glucose levels (hyperglycemia), which result in heart, kidney and eye diseases, amputations and neurological impairment. Unfortunately, there are very real and serious complications associated with use of medications used to treat the diabetes-related hyperglycemia. One of the most common complications of treatments used to reduce blood sugar levels is hypoglycemia (low blood sugar), most frequently seen in patients being treated with insulin (i.e., all persons with type 1 diabetes and approximately 30% of patients with type 2 diabetes) but also in patients with type 2 diabetes receiving sulfonylurea treatment. Indeed, if it was not for the barrier of hypoglycemia, people with diabetes could probably have normal blood glucose levels and thus avoid the complications associated with hyperglycemia (Cryer, 2002).
Depending on the severity of the episode, hypoglycemia causes a wide range of physical problems ranging from weakness, dizziness, sweating, chills and hunger to more serious symptoms including blurred vision, behavior change, seizures, coma and even death. In addition to the physical effects of hypoglycemia, there are significant psychological effects including embarrassment, fear of another episode, high levels of anxiety and low levels of overall happiness that adversely affect glucose control and quality of life (Deary, 2008).
Severe hypoglycemia in a conscious person should be treated by the oral ingestion of carbohydrate, preferably as glucose tablets or equivalent. For severe hypoglycemia in an unconscious individual outside of the hospital setting, the recommended treatment is 1 mg of glucagon by intramuscular (IM) or subcutaneous (SC) injection. For severe hypoglycemia in an unconscious individual in the presence of professional medical assistance and intravenous access, intravenous dextrose is recommended. In all cases, once the hypoglycemia has been reversed, the patient should be given access to oral carbohydrates to fully recover and prevent repeated hypoglycemia.
Glucagon, a highly effective treatment for severe hypoglycemia both outside and within the hospital setting, is currently available only as a powder that must be mixed with a diluent immediately prior to administration by injection. Although this is a procedure that would be relatively easy for people with diabetes who inject insulin, they are not treating themselves because, by definition, severe hypoglycemia is a hypoglycemic episode in which the patient requires third party assistance (Cryer, 2009). For any non-medical person who is confronted with an emergency situation in which a patient with diabetes is in a hypoglycemic coma or suffering hypoglycemia-related convulsions, reconstitution and injection of the current injectable glucagon is a complex and daunting procedure that is fraught with potential for errors.
Indeed, Australian researchers have published a study in which parents of children and adolescents with diabetes used one of the currently available glucagon kits (GlucoGen Hypokit, Novo Nordisk) in a simulated emergency situation (Harris et al, 2001). Each parent was asked to pretend it was 3:00 am and their child was unconscious. They were then given an unopened emergency glucagon kit and asked to administer the medication in a wrapped piece of meat to simulate a thigh. A small of group of 11 diabetes health professionals (five endocrinologists and six diabetes educators) served as surrogate control.
Of the 136 parents who participated in the study, 106 were parents of teenagers with a mean duration of diabetes of 4.7 years and 30 were parents of younger children with a mean duration of diabetes of 2.4 years. Over 90% reported having been previously trained on use of glucagon. Fully 69% of these parents experienced difficulties handling the current glucagon emergency kit. Difficulties included difficulty in opening the pack, removal of the needle sheath, mixing of the ingredients and bending of needles. On average, these parents required 2 minutes and 30 seconds to complete the procedure (range 30 seconds to >12 minutes). In addition, 6% aborted the injection entirely and 4% of the participants injected only air or only diluent. In contrast, diabetes professionals performed the procedure in 1 minute and 17 seconds (range 1-1.75 minutes). The number of errors observed in this sample of parents is disconcerting especially in light of the fact that this was a timed simulation and not a true emergency.
Difficulties associated with use of the glucagon emergency kit are corroborated in a recent report from the Institute for Safe Medication Practices (ISMP) Canada (ISMP Canada Safety Bulletin, 2010). The ISMP report of September 2010 documents three separate incidents in which the diluent was administered on its own, without the glucagon powder having been reconstituted with the diluent before administration. This resulted in complete failure to deliver the intended dose of glucagon to individuals experiencing a severe hypoglycemic crisis and, according to the report, resulted in patient harm in one of the cases.
A telephone survey was conducted with 102 patients with type 1 diabetes to ascertain their opinions on the currently available glucagon emergency kits (Yanai, 1997). Most patients (67%) stated they would prefer an intranasally administered glucagon were it available and fully 82% of these patients assumed family members, teachers and colleagues would prefer to administer emergency therapy by the intranasal route. Likewise, amongst emergency care professionals who are frequently the first to be called to treat a patient suffering from an episode of severe hypoglycemia, there is significant concern regarding the injected route of administration. Inherent in using sharps, there is the very real risk of accidental blood exposure and needlestick and the associated potential for contracting life-threatening infectious diseases (Leiss J 2006). Within this context, some emergency professionals are actively seeking noninvasive routes of administration, including intranasal, as a means to enhance emergency patient care, increase patient and care-giver safety while increasing the pool of care providers who can effectively respond to the emergency (Curran, 2007).
These considerations make it clear that the present approach to the administration of glucagon in emergency situations is lacking, and that there exists a real need for alternative approaches for delivering glucagon to treat severe hypoglycemia.
Various approaches to delivery of glucagon via intranasal administration have been proposed but they have not resulted in the availability of an approved alternative to injected glucagon. In general, these approaches can be divided into two groups, those that use administer a liquid formulation, and those that use some type of dry formulation.
Within the liquid formulations group, the compositions used in Pontiroli (1983), Pontiroli (1985), Freychet (1988), Pontiroli (1989), Pontiroli (1993) and Pacchioni (1995) were all formulations that needed to be sprayed into the nose. More recently, Sibley et al., 2013, reported successful use of what was intended to be injectable glucagon by spraying the reconstituted glucagon solution intranasally in a patient in the out-of-hospital environment.
Because glucagon is not stable in the liquid state, the liquid compositions used in these studies needed to be reconstituted immediately prior to use and are therefore not ideal for emergency use in treating severe hypoglycemia. Further, in many of these studies, patients needed to take a deep breath immediately after dosing with these compositions. Since patients with severe hypoglycemia are frequently unconscious or even comatose, they cannot be asked to take a deep breath. As such, these compositions are not ideal for intranasal delivery for treatment of severe hypoglycemia, and do not overcome the challenges of injectable formulations that involve use of a needle by non-medical professionals and need to be prepared prior to use.
Within the second group, U.S. Pat. No. 5,059,587 discloses powders for nasal administration of physiologically active peptides, including glucagon. These powders include a water-soluble organic acid as an absorption promoter.
Jorgensen et al. 1991 disclosed a “powdery formulation of glucagon for nasal delivery.” This formulation is disclosed as containing glucagon, didecyl phosphatidylcholine (DDPC) and α-cyclodextrin (α-CD), and is reported as providing a dosage dependent response with respect to increases in plasma glucose and plasma glucagon. No compositional amounts or method of making the formulation are disclosed in this reference.
The Jorgensen 1991 formulation or HypoGon® Nasal (NovoNordisk) is identified as the material used in several subsequent studies, and in one of these reports the formulation is said to have a composition of glucagon:DDPC: α-CD in a 5:10:85 ratio by weight. In these studies, intranasal administration to adults of the Jorgensen 1991 powder formulation is reported to show an increase in plasma glucose concentration in adults with hypoglycemia. In these studies, glucose levels increased after dosing to reach a plateau at about 30 minutes after dosing. In contrast, treatment with injected glucagon in these studies resulted in glucose levels that continued to increase from the time of administration for up to at least 90 minutes (Hvidberg, 1994; Rosenfalck, 1992). Intranasal administration to children with hypoglycemia of the Jorgensen 1991 powder formulation is reported to increase plasma glucose concentration soon after dosing to peak levels 25-30 minutes post-dosing after which glucose levels decreased. In contrast, treatment of children with injected glucagon resulted in plasma glucose levels that continued to rise for at least 45 minutes (Stenninger, 1993).
Sakr, 1996 reports a comparison of spray and powder formulations containing glucagon and dimethyl-β-cyclodextrin (DMβCD). Nasal spray was prepared by dissolving commercial glucagon in the “manufacturer's solvent” containing 2 or 5% w/v DMβCD. Powders were obtained by freeze drying of the spray solutions.
Teshima et al (2002) found that a maximum plasma glucose increase of 1.56 mmol/L (28.08 mg/dL) in healthy volunteers upon intranasal administration of a powder containing glucagon and microcrystalline cellulose at a ratio of 1:69. They also reported that the powder form is stable at 5 and 25° C. for at least 84 days. For an intranasal product in patients with insulin-induced hypoglycemia, an increase of only 1.5 mmol/L may be inadequate to bring the patient back to normal blood glucose levels. In addition, the volume of powder (i.e., 70 mg for a 1:69 ratio formulation) is considerable and may be excessive for use with available devices.
Matilainen et al (2008, 2009) investigated the solid-state stability and dissolution of glucagon/γ-CD and glucagon/lactose powders at an increased temperature and/or humidity for up to 39 weeks, with the solid state stability of the glucagon/γ-CD powder being better. The powder was not used for intranasal administration.
Endo et al (2005) reported that the use of erythritol as both an excipient and a carrier in a dry-powder inhaler of glucagon for pulmonary administration. The powder was formulated by mixing micronized glucagon particles and excipients with larger carrier particles. To achieve alveolar deposition for subsequent systemic absorption, a dry powder inhalant (DPI) of glucagon was size-reduced to a mass median diameter between 1 and 6 micron, as measured by laser diffraction analysis.
Onoue et al (2009) reported that addition of citric acid in glucagon dry-powder inhaler for pulmonary inhalation improved the dissolution behavior, and did not impair the solid-state stability. Intratracheal administration of glucagon dry-powder inhaler (50 μg/kg in rats) containing citric acid led to 2.9-fold more potent hyperglycemic effect in rats, as compared to inhaled glucagon without citric acid. Both the Endo (2005) and Onoue (2009) disclosures present pulmonary delivery of glucagon. As patients with severe hypoglycemia may be unconscious or severely disoriented, they cannot be expected to breathe deeply to assure pulmonary delivery. As such, pulmonary delivery of glucagon is not appropriate for treatment of severe hypoglycemia.
Notwithstanding these efforts, no current product is available to patients that utilizes a nasal powder to administer glucagon for the treatment of severe hypoglycemia.
It is an object of the present invention to provide such a nasal powder formulation.